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Metagenomic methods for the analysis of human microbiota towards a clinical application.
Full text linkSeveral microbial communities colonize different body areas constituting the human microbiota.
Recently, several researches suggested the involvement of these bacteria in maintaining omeostasis of the human body, highlighting as a microbial dysbiosis may be implicated in numerous inflammatory conditions and human diseases. The high-throughput sequencing technologies applicate to the study of human microbiome allowed to achieve important results about the interactions between microorganisms and the host. Moreover, metagenomics studies extended scientists’ knowledge about the human microbiota and its implications in numerous human diseases. Since the 16S rRNA gene sequencing was shown to be an effective method to investigate microbial communities, recently our laboratory adopted this molecular approach to characterize the interactions between bacteria and host. Therefore, the present PhD work describes our experience in samples collection, experimental procedures and data analysis in studying the human microbiota by means of a metagenomics approach. Indeed, our studies allowed us to understand that to achieve a complete overview of microbial communities involved in a specific fisio-pathological condition, a standardization of experimental protocols and data analysis should be adopted to carry out metagenomics surveys. Moreover, the taxonomic evaluations through 16S rRNA gene sequencing are just a first step for elucidating the roles of bacteria in the host’s health. Integrating the metagenomics data which those obtained by metatranscriptomic, metaproteomic, and metametabolomic represents a promising approach to develop new noninvasive bacterial-related diagnostic tools
Improving sustainability of sediment management in Alpine reservoirs: control of sediment flushing operations to mitigate downstream environmental impacts.
Full text linkThis thesis focuses on the desiltation of Alpine reservoirs in order to sustain their long-term utilization and restore the functioning of the bottom outlets, minimizing at the same time downstream environmental impacts of sediment removal operations. Different case studies of controlled sediment flushing operations (CSFs) are analysed adopting a multidisciplinary approach. In particular, sediment transport and downstream riverbed alteration, ecological impacts on benthic macroinvertebrates and fish, and performance indicators were investigated. Moreover, the experimental dataset acquired before, during, and after a sediment removal operation was used to carry out and calibrate a one-dimensional sediment transport model of the monitored event. The duration of the CSFs and the average suspended sediment concentration in the outflowing water were constrained, with the specific environmental objective of limiting the downstream fish mortality as predicted by a simple dose/response model. The biomonitoring indicated that this model allowed for a first approximation estimate of the impacts on trout. On the other hand, similar scenarios of sediment removal in terms of duration and average SSC can be identified with analogous predicted impacts on fish but non-negligible differences in flushing efficiency. Therefore, site-specific investigation of environmental impacts may be the key aspect for upgrading the trade-off between economic and environmental needs in planning further operations in the same area
Development of a silicon photomultiplier based innovative and low cost positron emission tomography scanner.
Full text linkThe Silicon Photomultiplier (SiPM) is a state-of-the-art semiconductor photodetector consisting of a high density matrix (up to 104) of independent pixels of micro-metric dimension (from 10 μm to 100 μm) which form a macroscopic unit of 1 to 6 mm2 area. Each pixel is a single-photon avalanche diode operated with a bias voltage of a few volts above the breakdown voltage. When a charge carrier is generated in a pixel by an incoming photon or a thermal effect, a Geiger discharge confined to that pixel is initiated and an intrinsic gain of about 106 is obtained. The output signal of a pixel is the same regardless of the number of interacting photons and provide only a binary information. Since the pixels are arranged on a common Silicon substrate and are connected in parallel to the same readout line, the SiPM combined output response corresponds to the sum of all fired pixel currents. As a result, the SiPM as a whole is an analogue detector, which can measure the incoming light intensity.
Nowadays a great number of companies are investing increasing efforts in SiPM detector performances and high quality mass production. SiPMs are in rapid evolution and benefit from the tremendous development of the Silicon technology in terms of cost production, design flexibility and performances. They have reached a high single photon detection sensitivity and photon detection efficiency, an excellent time resolution, an extended dynamic range. They require a low bias voltage and have a low power consumption, they are very compact, robust, flexible and cheap. Considering also their intrinsic insensitivity to magnetic field they result to have an extremely high potential in fundamental and applied science (particle and nuclear physics, astrophysics, biology, environmental science and nuclear medicine) and industry.
The SiPM performances are influenced by some effects, as saturation, afterpulsing and crosstalk, which lead to an inherent non-proportional response with respect to the number of incident photons. Consequently, it is not trivial to relate the measured electronic signal to the corresponding light intensity. Since for most applications it is desirable to qualify the SiPM response (i.e in order to properly design a detector for a given application, perform corrections on measurements or on energy spectra, calibrate a SiPM for low light measurements, predict detector performance) the implementation of characterization procedures plays a key role.
The SiPM field of application that has been considered in this thesis is the Positron Emission Tomography (PET). PET represents the most advanced in-vivo nuclear imaging modality: it provides functional information of the physiological and molecular processes of organs and tissues. Thanks to its diagnostic power, PET has a recognized superiority over all other imaging modalities in oncology, neurology and cardiology. SiPMs are usually successfully employed for the PET scanners because they allow the measurement of the Time Of Flight of the two coincidence photons to improve the signal to noise ratio of the reconstructed images. They also permit to perfectly combine the functional information with the anatomical one by inserting the PET scanner inside the Magnetic Resonance Imaging device.
Recently, PET technology has also been applied to preclinical imaging to allow non invasive studies on small animals. The increasing demand for preclinical PET scanner is driven by the fact that small animals host a large number of human diseases. In-vivo imaging has the advantage to enable the measurement of the radiopharmaceutical distribution in the same animal for an extended period of time. As a result, PET represents a powerful research tool as it offers the possibility to study the abnormalities at the origin of a disease, understand its dynamics, evaluate the therapeutic response and develop new drugs and treatments. However, the cost and the complexity of the preclinical scanners are limiting factors for the spread of PET technology: 70-80% of small-animal PET is concentrated in academic or government research laboratories.
The EasyPET concept proposed in this Thesis, protected under a patent filed by Aveiro University, aims to achieve a simple and affordable preclinical PET scanner. The innovative concept is based on a single pair of detector kept collinear during the whole data acquisition and a moving mechanism with two degrees of freedom to reproduce the functionalities of an entire PET ring. The main advantages are in terms of the reduction of the complexity and cost of the PET system. In addition the concept is bound to be robust against acollinear photoemission, scatter radiation and parallax error. The sensitivity is expected to represent a fragility due to the reduced geometrical acceptance. This drawback can be partially recovered by the possibility to accept Compton scattering events without introducing image degradation effects, thanks to the sensor alignment.
A 2D imaging demonstrator has been realized in order to assess the EasyPET concept and its performance has been analyzed in this Thesis to verify the net balance between competing advantages and drawbacks. The demonstrator had a leading role in the outreach activity to promote the EasyPET concept and a significant outcome is represented by the new partners that recently joined the collaboration. The EasyPET has been licensed to Caen S.p.a. and, thanks to the participation of Nuclear Instruments to the electronic board re-designed, a new prototype has been realized with additional improvements concerning the mechanics and the control software. In this Thesis the prototype functionalities and performances are reported as a result of a commissioning procedure. The EasyPET will be commercialized by Caen S.p.a. as a product for the educational market and it will be addressed to high level didactic laboratories to show the operating principles and technology behind the PET imaging.
The topics mentioned above will be examined in depth in the following Chapters according to the subsequent order. In Chapter 1 the Silicon Photomultiplier will be described in detail, from their operating principle to their main application fields passing through the advantages and the drawback effects connected with this type of sensor. Chapter 2 is dedicated to a SiPM standard characterization method based on the staircase and resolving power measurement. A more refined analysis involves the Multi-Photon spectrum, obtained by integrating the SiPM response to a light pulse. It exploits the SiPM single photon sensitivity and its photon number resolving capability to measure some of its properties of general interest for a multitude of potential applications, disentangling the features related to the statistics of the incident light. Chapter 3 reports another SiPM characterization method which implements a post-processing of the digitized SiPM waveforms with the aim of extracting a full picture of the sensor characteristics from a unique data-set. The procedure is very robust, effective and semi-automatic and suitable for sensors of various dimensions and produced by different vendors. Chapter 4 introduces the Positron Emission Tomography imaging: its principle, applications, related issues and state of the art of PET scanner will be explained. Chapter 5 deals with the preclinical PET, reporting the benefits and the technological challenges involved, the performance of the commercially available small animal PET scanners, the main applications and the frontier research in this field. In Chapter 6 the EasyPET concept is introduced. In particular, the basic idea behind the operating principle, the design layout and the image reconstruction will be illustrated and then assessed through the description and the performance analysis of the EasyPET proof of concept and demonstrator. The effect of the use of different sensor to improve the light collection and the coincidence detection efficiency, together with the analysis of the importance of the sensor and the crystal alignment will be reported in Chapter 7. The design, the functionalities and the commissioning of the EasyPET prototype addressed to the educational market will be defined in Chapter 8. Finally, Chapter 9 contains a summary of the conclusions and an outlook of the future research studies
Multigrid methods and stationary subdivisions
Full text linkMultigridmethods are fast iterative solvers for sparse large ill-conditioned linear systems of equations derived, for instance, via discretization of PDEs in fluid dynamics, electrostatics and continuummechanics problems. Subdivision schemes are simple iterative algorithms for generation of smooth curves and surfaces with applications in 3D computer graphics and animation industry.
This thesis presents the first definition and analysis of subdivision based multigrid methods.
The main goal is to improve the convergence rate and the computational cost of multigrid taking advantage of the reproduction and regularity properties of underlying subdivision.
The analysis focuses on the grid transfer operators appearing at the coarse grid correction step in the multigrid procedure. The convergence of multigrid is expressed in terms of algebraic properties of the trigonometric polynomial associated to the grid transfer operator. We interpreter the coarse-to-fine grid transfer operator as one step of subdivision. We reformulate the algebraic properties ensuring multigrid convergence in terms of regularity and generation properties of subdivision. The theoretical analysis is supported by numerical experiments for both algebraic and geometric multigrid. The numerical tests with the bivariate anisotropic Laplacian ask for subdivision schemes with anisotropic dilation. We construct a family of interpolatory subdivision schemes with such dilation which are optimal in terms of the size of the support versus their polynomial generation properties. The numerical tests confirmthe validity of our theoretical analysis
Smooth path planning with Pythagorean-hodoghraph spline curves geometric design and motion control
Full text linkThis thesis addresses two significative problems regarding autonomous systems, namely path and trajectory planning. Path planning deals with finding a suitable path from a start to a goal position by exploiting a given representation of the environment. Trajectory planning schemes govern the motion along the path by generating appropriate reference (path) points.
We propose a two-step approach for the construction of planar smooth collision-free navigation paths. Obstacle avoidance techniques that rely on classical data structures are initially considered for the identification of piecewise linear paths that do not intersect with the obstacles of a given scenario.
In the second step of the scheme we rely on spline interpolation algorithms with tension parameters to provide a smooth planar control strategy. In particular, we consider Pythagorean–hodograph (PH) curves, since they provide an exact computation of fundamental geometric quantities. The vertices of the previously produced piecewise linear paths are interpolated by using a G1 or G2 interpolation scheme with tension based on PH splines. In both cases, a strategy based on the asymptotic analysis of the interpolation scheme is developed in order to get an automatic selection of the tension parameters.
To completely describe the motion along the path we present a configurable trajectory planning strategy for the offline definition of time-dependent C2 piece-wise quintic feedrates. When PH spline curves are considered, the corresponding accurate and efficient CNC interpolator algorithms can be exploited
Endometrial carcinomas with mismatch repair deficiency: immunophenotypical and molecular characterization.
Full text linkThis project was focused on the molecular and immunophenotypical characterization of a series of 80 gynecological cancers (GC, 64 endometrial, 12 ovarian, 4 endocervical) from patients who referred to the Cancer Genetic Counseling of Varese Hospital. We investigated the immunohistochemical (IHC) expression of MMR proteins, the microsatellite (MSI) profile of GC. We observed that the IHC analysis identified more cases with MMR deficit respect to the MSI analysis, in particular we identified a subgroup of cases with a borderline MSI profile. In order to improve MSI test, we tested four additional MSI target loci (RPL22, SRPR, MBD6 and NRIP) by setting up the MSI test in our series, these analysis revealed RPL22 and SRPR as informative loci in borderline cases and provided MSI evaluation criteria. We also analyzed MLH1 promoter methylation profile in MLH1 IHC negative samples to distinguish the sporadic MLH1 negative samples to LS cases. We set up the IHC analysis of ARID1A protein. We observed ARID1A protein loss in LS cancers, respect to sporadic cancer. Finally, we investigated the mutational landscape of 16 genes involved in endometrial cancer by targeted exome sequencing in 35 endometrial cancers. The genes most frequently mutated were ARID1A, ARID2, PTEN. The MSI cases show a higher mutational rate respect to MSS samples
Genomic aberrations in acute myeloid leukemia and significance of constitutional copy number variations in the development of post-transplant lymphoproliferative disorders.
Full text linkIn the first part of this study, 22 AML patients with Normal Karyotype were retrospectively analyzed by using OGT Hematological Cancer 8x60K CGH+ SNP array, in order to detect cryptic genomic aberrations.
11 out of 22 patients confirmed a normal genomic setting;11 out of 22 patients instead showed unexpected genomic imbalances, such as trisomies (+4, +8, +10, +13, +16) or monosomies (-7, -5q, -Y).
In addition to this large rearrangements, some patients showed Copy Number Variations (CNVs) containing genes involved in hematological process or tumorigenesis.
aCGH was also performed in a small group of patients with Complex karyotype in order to better define the cytogenetic results and to detect cryptic CNVs.
This study suggests a potential role for the use of aCGH in the clinical workup of AML patients with Normal karyotype in order to identify cryptic leukemic clones.
In the future this new approach will probably permit to better stratify the patients in risk category and make a more appropriate therapy.
In the second part of the study,22 renal-transplated patients were tested with OGT Oligoarray platform 4x180K CGH array in order to evaluate constitutional CNVs that might predispose to post-transplant lymphoproliferative disease.
Constitutional chromosomal regions involved in genomic imbalances (CNVs) affected mostly regions containing oncogenes or critical hematological regions,such as: 1p21.1,6p25.31, 14q32.33, and 16p11.2. These copy number variations are exclusively described in patients who develop PTLD and patients without PTLD but with High-EBV viral Load, and thus, at risk to develop the disease. This study permitted to identify new candidate loci involved in the predisposition of PTLD-development
Multi-wavelength observations of variability characterizing magnetic activity in late-type stars.
No full textThe presence of magnetic fields in the atmosphere of the late-type stars determines the formation of small scale structures which make the atmosphere inhomogenous, causes excess heating of the atmospheric plasma with consequent excess thermal radiation, and also non-thermal radiation. This is what is referred to as magnetic activity, which gives essential information on the properties of the stellar magnetic fields and internal dynamos.
In the first work I present, I characterize the relation between magnetic activity (mainly X-ray activity) and the stellar rotation, which is a proxy for the internal dynamo mechanism of stars. For the first time, the measure of rotation period and of the X-ray activity is carried on in a fully homogeneous way on the whole sample. The results I obtain confirms previous results.
In the second work, I present the discovery of strong magnetic activity, in the form of an X-ray flare, from a very young (Class I) YSO, ISO-Oph 85; this latter work is focused on the characterization of this transient X-ray emission and on the classification of he evolutionary stage of ISO-Oph 85.
In this works, the study of X-ray activity plays a major role. The X-ray data I use are taken from the XMM-Newton observatory. I take advantage, for the time-resolved analsyis of the X-ray data, of algorithms and products by the EXTraS Project. In the first one of the two works presented, the observations performed by the Kepler mission have a crucial role
Prove legali e libero convincimento
Full text linkAfter having re read both the method of the free conviction and that of the legal evidence under the historical – philososophical light, the thesis proposes to analyse and verify the efficiency of the rule of judgement of the (relatively new) code of criminal procedure. The experiences in term of the Rocco code through which the intime conviction had legitimated the use of the diverse probatory materials obtained, even in disregard of the fondamental human rights, are well known. The study examines if and in what measure the actual regulatory framework inspired by the free convinction, that has reconfigure the entire probatory system, is suitable to circumscribe those deviated judicial practices and to guarantee a just sentence. Under this reconstruction, the thesis analyses the evidentiary methods used by the judge even in relation to the so called scientific proof. Following the said analysis, the deduction is that to reach a just sentence it is necessary to retrive both the tradition of proof as argomentum and the probatory rules which, without detracting anything from the intime conviction, allow to regulate the probatory materials in the judge’s hands in the respect of the fundamental human rights, surpassing the disrepute commonly associated with the concept of “legal proof”
Vocazione polifunzionale del sequestro penale e problematica valutazione del fumus commissi delicti.
Full text linkThe matter of the research deals with the elements of fact and law which allow garnishments and other forms of attachment in the Italian criminal procedure. Particularly, it refers to the fumus commissi delicti element, applied due to the purpose and the rights involved in the specific measure ordered by the Court.
The dissertation starts with a chronological analysis (Criminal Procedure Code of 1930) in order to make clear how the actual forms of seizure and confiscating originate in the Italian criminal procedure. They are rather distinguishable, according to their aim, in seizure for evidentiary purposes (Criminal Procedure Code, Article 253), conservative seizure (Criminal Procedure Code, Articles 316 et seq.) and preventive seizure (Criminal Procedure Code, Articles 321 et seq.).
All the measures of attachment affect the fundamental rights, as the private propriety and the economic freedom (Constitution, Articles 41 and 42) and the freedom of expression (Constitution, Article 21). The legislative power shall find a balance between the protection of Constitutional rights and the necessity of ensuring the protective and evidentiary purposes of a measure limiting rights.
The analysis focuses on the peculiarity of the fumus, the most important element in balancing fundamental rights with the purposes of criminal procedure. In case of seizure for evidentiary purposes, the fumus determines whether a criminal offence may figuratively exist, since the prior necessity is to perpetuate secure evidence.
In case of preventive seizure, as the jurisprudence of the Supreme Court of Cassation appoints, the mere verification of the fumus is not enough.
The attachment has the same enforcement of the personal coercive measures, since it affects the fundamental rights, in order to prevent the deterioration in the consequences of a crime or the commission of any further criminal offence.The peculiarity of the fumus shall be meant not in an inquiry view, but in the sense of the “serious evidence of a crime”, granting an effective control upon the Public Prosecutor’s suit and the exercise of the rights of defence